The present invention relates to compounds that are shown to be potent cyclin/cyclin dependent kinase (cdk) inhibitors. Compounds with these properties are shown to be potent inhibitors of cell growth and proliferation. Such compounds can be used to treat the following conditions: rheumatoid arthritis, lupus, type 1 diabetes, multiple sclerosis, cancer, restenosis, gout and other proliferative diseases involving abnormal cellular proliferation. Compounds of the present invention which are biaryl substituted purine derivatives are shown to be potent antiproliferative agents against a number of human transformed cell lines, and also inhibitors of human cyclin/cdk kinase complexes.
Cellular Proliferation and Cancer
The disruption of external or internal regulation of cellular growth can lead to uncontrolled proliferation and in cancer, tumor formation. This loss of control can occur at many levels and, indeed, does occur at multiple levels in most tumors. Further, although tumor cells can no longer control their own proliferation, they still must use the same basic cellular machinery employed by normal cells to drive their growth and replication.
Cyclin Dependent Kinases and Cell Cycle Regulation
Progression of the normal cell cycle from the G1 to S phase, and from the G2 phase to M phase is dependent on cdks (Sherr, C. J., Science 274:1672-1677 (1996)). Like other kinases, cdks regulate molecular events in the cell by facilitating the transfer of the terminal phosphate of adenosine triphosphate (ATP) to a substrate protein. Isolated cdks require association with a second subunit, called cyclins (Desai et al., Mol. Cell. Biol., 15:345-350 (1995)). Cyclins cause conformational changes at the cdk active site, allowing ATP access and interaction with the substrate protein. The balance between its rates of synthesis and degradation controls the level of each cyclin at any point in the cycle (Elledge, S. J., et al., Biochim. Biophys. Acta, 1377:M61-M70 (1998)). The influences of cyclin/cdk activity on the cell cycle and cellular transformation are summarized in Table 1.
Abnormal Cyclin/cdk Activity in Cancer
In a normal cell, interlocking pathways respond to the cell""s external environment and internal checkpoints monitor conditions within the cell to control the activity of cyclin/cdk complexes. A reasonable hypothesis is that the disruption of normal control of cyclin/cdk activity may result in uncontrolled proliferation. This hypothesis appears to hold in a number of tumor types in which cyclins are expressed at elevated levels (Table 1). Mutations in the genes encoding negative regulators (proteins) of cyclin/cdk activity are also found in tumors (Larsen, C.-J., Prog. Cell Cycle Res., 3:109-124 (1997)); (Kamb, A., Trends in Genetics, 11:136-140 (1995)). Members of the Cip family of cdk inhibitors form a ternary complex with the cyclin/cdk and require binding to cyclinA, cyclinE, or cyclinD (Hall, M., et al., Oncogene, 11:1581-1588 (1995)). In contrast, Ink family members form a binary complex with cdk4 or cdk6 and prevent binding to cyclinD (Parry, D.; et al., EMBO J., 14:503-511 (1995)).
Inhibitors of Cyclin/cdk Complexes as Potential Anticancer Agents
Tumors with elevated cyclin/cdk activity, whether from the over expression of cyclins or the loss of an endogenous cdk inhibitor, are prime targets for potential therapies based on small molecule cyclin/cdk inhibitors. In fact, several small molecule inhibitors of cyclin/cdks are reported (Meijer, L., et al., xe2x80x9cProgress in Cell Cycle Research,xe2x80x9d Plenum Press: New York, 351-363 (1995)) and appear to bind at the ATP site of the kinase. Some information is known about small molecule inhibitors of other kinases, such as PKC (serine kinase) (Murray, K. J. et al., xe2x80x9cAnn. Rep. Med. Chem.,xe2x80x9d J. Bristol, Ed., Academic Press, Inc.: New York, Chapter 26 (1994)) and tyrosine kinases (Fatl, W. J., et al., Ann. Rev. Biochem., 62:453 (1993); Burke, T. R., Drugs of the Future, 17:119-1131 (1992); Dobrusin, E. M. et al., xe2x80x9cAnn. Rep. Med. Chem,xe2x80x9d J. Bristol, Ed., Academic Press, Inc.: New York, Chapter 18 (1992); Spence, P., Curr. Opin. Ther. Patents, 3:3 (1993)). A number of known inhibitors were obtained from commercial sources or were synthesized by literature procedures.
Purine Compounds as Cyclin/cdk Inhibitors
There are several reports of 2,6-diamino substituted purine derivatives as cyclin/cdk inhibitors and as inhibitors of cellular proliferation. Among those are reports by U.S. Pat. No. 5,583,137 to Coe, et al., olomoucine (Vesely, J., et al., Eur. J. Biochem., 224:771-786 (1994)), roscovitine (Meijer, L., Eur. J. Biochem., 243:527-536 (1997)), WO 97/16452 to Zimmerman, Imbach, P., et al., Bioorg. Med. Chem. Lett., 9:91-96 (1999), Norman, T. C., et al., J. Amer. Chem. Soc., 118:7430-7431 (1996), Gray, N. S., et al., Tetrahedron Lett., 38:1161-1164 (1997), Gray, N. S., et al., Science, 281:533-538 (1998), WO 98/05335 to Lum, et al., Schow, S. R., et al., Bioorg. Med. Chem. Lett, 7:2697-2702 (1997), U.S. Pat. No., 5,886,702 to Mackman, et al., Nugiel, D. A., et al., J. Org. Chem., 62:201-203 (1997), and Fiorini. M. T. et al., Tetrahedron Lett., 39:1827-1830 (1998). Many of these reported compounds are shown to inhibit cyclin/cdk complexes and have modest cellular proliferation inhibition properties.
The compounds of the present invention are shown to have far superior biological activities as cyclin/cdk complex inhibitors as well as inhibitors of cellular proliferation compared to those previously reported. In fact, the art (e.g., Fiorini, M. T. et al., Tetrahedron Lett., 39:1827-1830 (1998)) teaches away fiom compounds of this invention, claiming lack of cellular proliferation inhibition.
The compounds of the present invention are 2,6,9-trisubstituted purine derivatives which are inhibitors of cyclin/cdk complexes. The compounds of the current invention also are potent inhibitors of human cellular proliferation. As such. the compounds of the present invention constitute pharmaceutical compositions with a pharmaceutically acceptable carrier. Such compounds are useful in inhibiting cellular proliferation in a mammal by administering to such mammal an effective amount of the compound.
In one embodiment, the compounds of the present invention are represented by the chemical structure found in Formula I 
wherein:
R1 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
X=
N;
CH;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
R3 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form a 5-8-membered ring;
n=0-3;
Y=
H;
OR1;
NHR1;
NHC(O)R3;
NHSO2R3;
NHC(O)NHR3;
NHC(O)R5;
NHC(O)OR6;
R5=C3-C7-cycloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
or a pharmaceutically acceptable salt thereof,
with the proviso that when R1=CH(CH3)2, and R2=Ph, and X=CH, then R3xe2x89xa0H, and nxe2x89xa00, and R4xe2x89xa0H and Yxe2x89xa0OH.
Another aspect of the present invention is directed to a compound of the following formula: 
wherein:
R1 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
X=
N;
CH;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
Y=
OR1;
NHR1;
NHC(O)R1;
NHSO2R1;
NHC(O)NHR1;
NHC(O)OR6; or a pharmaceutically acceptable salt thereof,
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
or a pharmaceutically acceptable salt thereof.
The present invention is also directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1=
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
X=
N;
CH;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents are in any position and are selected from Br, Cl, F, R1, C(O)CH3;
R3=
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form a 5-8-membered ring;
n=0-3;
Y=
H;
OR1;
NHR1;
NHC(O)R3;
NHSO2R3;
NHC(O)NHR3;
NHC(O)R5;
NHC(O)OR6;
R5=C3-C7-cYcloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2; or a pharmaceutically acceptable salt thereof
with the proviso that when R1=CH(CH3)2, and R2=Ph, and X=CH, then R3xe2x89xa0H, and nxe2x89xa00, and R4xe2x89xa0H, and Yxe2x89xa0OH, said process comprising:
reacting a compound of the formula: 
xe2x80x83with a compound of the formula: 
under conditions effective to form the purine derivative compound.
Another aspect of the present invention is directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
X=
N;
CH;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are selected from Br, Cl, F, R1, C(O)CH3;
R3 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form a 5-8-membered ring;
n=0-3;
Y=
H;
OR1;
NHR1;
NHC(O)R3;
NHSO2R3;
NHC(O)NHR3;
NHC(O)R5;
NHC(O)OR6;
R5=C3-C7-cycloalkyl;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2; or a pharmaceutically acceptable salt thereof,
with the proviso that when R1=CH(CH3)2 and R2=Ph and X=CH, then R3xe2x89xa0H, and nxe2x89xa00, and R4xe2x89xa0H, and Yxe2x89xa0OH, said process comprising:
reacting a compound of the formula: 
xe2x80x83wherein
Z=Br or I
with a compound of the formula: R2xe2x80x94B(OH)2, R2xe2x80x94Sn(n-Bu)3, R2xe2x80x94Sn(Me)3, or mixtures thereof, under conditions effective to form the purine derivative compound.
The compounds of the present invention, as described in Formula I, show significantly improved growth inhibition of human transformed cell lines and/or cyclin/cdk inhibition relative to compounds of the prior art. These compounds have been demonstrated to be potent growth inhibitors in dozens of human transformed cell lines. Olomoucine, a structurally related purine derivative, is a poor human transformed cell growth inhibition agent with GI50 values in the 20,000-100,000 nM range over 60-transformed cell lines. By contrast, the compounds of the present invention demonstrate GI50 values over 60-transformed cell lines in the  less than 10-25.000 nM range, preferably in the  less than 10-100 nM range over 60-transformed cell lines, and, most preferably,  less than 10 nM across 60-human transformed cell lines. This finding is unexpected from the prior art, which specifically teaches that compounds of the present invention would not be potent human transformed cell line growth inhibitors.
The R2 group in Formula I imparts unexpected and significant improvement in growth inhibition in human transformed cell lines, while substitution of various groups at R3 and R4 found in Formula I impart important features that contribute to cyclin/cdk inhibition and growth inhibition of human transformed cell lines. Specifically, the combination of the R2 group and the substitutions within R3 and R4 result in compounds with superior biological activity. Compounds which are cyclin/cdk inhibitors and/or human transformed cell line growth inhibitors have utility in treating human proliferative cellular disorders.
The compounds of the present invention are represented by the chemical structure found in Formula II. 
wherein:
R1 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
X=
N;
CH;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, Cl3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
R3 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R4=
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form a 5-8-membered ring;
n=0-3;
Y=
H;
OR1;
NHR1;
NHC(O)R3;
NHSO2R3;
NHC(O)NHR3; or a pharmaceutically acceptable salt thereof;
with the proviso that when R1=CH(CH3)2, and R2=Ph, and X=CH, then R3xe2x89xa0H, and nxe2x89xa00, and R4xe2x89xa0H, and Yxe2x89xa0OH.
More preferably, the compounds of the current invention are represented by the chemical structure found in Formula III. 
wherein:
R1 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
X=
N;
CH;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furan yl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
Y=
OR1;
NHR1;
NHC(O)R1;
NHSO2R1;
HC(O)NHR1;
NHC(O)OR6; or a pharmaceutically acceptable salt thereof;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention is directed to a method for inhibiting cellular proliferation in mammals comprising administering a therapeutically effective amount of the compound of the present invention to the mammal.
The compounds of the present invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes. They may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as. tablets, capsules, powders, solutions, suspensions, or emulsions.
Based on the results obtained in the standard pharmacological test procedures described below, the compounds of the present invention are useful as antineoplastic agents. More particularly, the compounds of the present invention are useful for inhibiting the growth of neoplastic cells, causing cell death of neoplastic cells, and eradicating neoplastic cells. The compounds of the present invention are, therefore, useful for treating solid tumors, including sarcomas and carcinomas, such as astrocytomas, prostate cancer, breast cancer, small cell lung cancer, and ovarian cancer, leukemias, lymphomas, adult T-cell leukemia/lymphoma. and other neoplastic disease states.
In addition to the utilities described above, many of the compounds of the present invention are useful in the preparation of other compounds.
The active compounds of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compound in these compositions may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 and 250 mg of active compound.
The tablets, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain. in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar, or both. A syrup may contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.
These active compounds may also be administered parenterallly. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The compounds of the present invention may also be administered directly to the airways in the form of an aerosol. For use as aerosols, the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.
General Synthetic Schemes
The compounds of the present invention can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequences outlined below are general methods useful for preparing the compounds of the present invention and are not meant to be limiting in scope or utility.
Reaction of 2,6-dichloropurine (Formula IV) with various amines of Formula V in the presence of a polar solvent, such as ethanol, provides purines of Formula VI (General Flowsheet I, infra). Reaction of purines of Formula VI with alkyl halides (R1xe2x80x94Z) in the presence of a base such as potassium carbonate provides N1-alkylated purines of Formula VII. Chloride displacement with N-alkylated purines of Formula VII with amines of structure Formula VIII in an inert solvent such as ethanol or butanol at an appropriate temperature provides purines of Formula IX. Transition metal-mediated cross-coupling reaction of purines of Formula IX with boronic acid (R2xe2x80x94B(OH)2) or tin reagents (R2xe2x80x94Sn(n-Bu)3 or R2xe2x80x94SnMe3) provides purines of Formula X. If in Formula X (Y=NH2), then subsequent reaction of Formula X (Y=NH2) with acid chloride (R3COCl), or sulfonyl chloride (R3SO2Cl). or isocyanate (R3NCO), or chloroformate (ClC(O)OR6) reagents provides purines of Formula XI wherein Y=NHC(O)R3, NHSO2R3, or NHC(O)NHR3, or NHC(O)OR6, respectively. On the other hand, if in Formula X, Y already is OR1 or NHC(O)R3 or NHSO2R3 or NHC(O)NHR3 or NHC(O)OR6, as a result of what Y started out as in Formula VIII, then this last step is unnecessary.
Definitions of the groups include:
R1 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
X=
N:
CH;
Z=
Br;
I;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
R3 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form a 5-8-membered ring:
n=0-3;
Y=
H;
OR1;
NHR1;
NHC(O)R3;
NHSO2R3;
NHC(O)NHR3;
NHC(O)OR6;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C3-C7-cycloalkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2. 
General non-limiting syntheses of compounds of the present invention of Formula XVIII and Formula XIX are shown below. 
Reaction of acids of Formula XII with oxalyl chloride or thionyl chloride followed by reaction with ammonium hydroxide provides amides of Formula XIII (General Flowsheet II). Transition metal-mediated cross-coupling reaction of amides of Formula XIII with boronic acid (R2xe2x80x94B(OH)2) or tin reagents (R2xe2x80x94Sn(n-Bu)3) or (R2xe2x80x94SnMe3) provides amides of Formula XIV. Reduction of amides of Formula XIV with a reducing agent in an appropriate solvent provides amines of Formula XV. Reaction of amines of Formula XV with 2,6-dichloropurine (Formula IV) in the presence of a polar solvent, such as ethanol, provides purines of Formula XVI. Reaction of purines of Formula XVI with alkyl halides (R1xe2x80x94Z) in the presence of a base such as potassium carbonate provides N1-alkylated purines of Formula XVII. Chloride displacement of purines of Formula XVII with amines of Formula VIII in an inert solvent such as ethanol or butanol at an appropriate temperature provides purines of Formula XVIII. If in Formula XVIII (Y=NH2), then subsequent reaction of Formula XVIII (Y=NH2) with acid chloride R3COCl), or sulfonyl chloride (R3SO2Cl), or isocyanate (R3NCO), or chloroformate (ClC(O)OR6) reagents provides purines of Formula XIX wherein Y=NHC(O)R3, or NHSO2R3, or NHC(O)NHR3, or NHC(O)OR6, respectively. On the other hand, if in Formula XVIII, Y already is OR1 or NHC(O)R3 or NHSO2R3 or NHC(O)NHR3 or NHC(O)OR6, as a result of what Y started out as in Formula VIII, then this last step is unnecessary.
Definitions of the groups include:
R1 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
X=
N;
CH;
Z=
Br;
I;
R2=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
R3 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form a 5-8-membered ring;
n=0-3;
Y=
H;
OR1;
NHR1;
NHC(O)R3;
NHSO2R3;
NHC(O)NHR3;
NHC(O)OR6;
R6=
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C3-C7-cycloalkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2.
The synthesis of compound 5 is shown below in Scheme I. 
The synthesis of compound 11 is shown below in Scheme II. 
The syntheses of compounds 12, 13 and 14 are shown below in Scheme III. 
The synthesis of compound 17 is shown below in Scheme IV. 
The synthesis of compound 17 is shown below in Scheme V. 
The synthesis of compound 25 is shown below in Scheme VI. 
The alternative synthesis of compound 25 is shown below in Scheme VII. 
The synthesis of compound 32 is shown below in Scheme VIII. 
The syntheses of compounds 33 and 34 are shown below in Scheme IX. 
The syntheses of compounds 36, 38, and 40 are shown below in Scheme X. 
The synthesis of compound 43 is shown below in Scheme XI. 
The synthesis of compound 46 is shown below in Scheme XII. 
The syntheses of compound 48 and 50 are shown below in Scheme XIII. 
The synthesis of compound 53 is shown below in Scheme XIV. 
The synthesis of compound 54 is shown below in Scheme XV. 
The synthesis of compound 56 is shown below in Scheme XVI. 
The synthesis of compound 58 is shown below in Scheme XVII. 
The synthesis of compound 60 is shown below in Scheme XVIII. 
The syntheses of compounds 61, and 62 are shown below in Scheme XIX. 
The syntheses of compounds 64, and 65 are shown below in Scheme XX. 
The syntheses of compounds 66, and 67 are shown below in Scheme XXI. 
The synthesis of compound 73 is shown below in Scheme XXII. 
The syntheses of compounds 74, 75, and 76 are shown below in Scheme XXIII. 
The synthesis of compound 77 is shown below in Scheme XXIV. 
The synthesis of compound 78 is shown below in Scheme XXV. 
An alternative synthesis of compound 78, and the synthesis of compound 79 are shown below in Scheme XXVI. 
The synthesis of compound 80 is shown below in Scheme XXVII. 
The syntheses of compounds 86, and 87 are shown below in Scheme XXVIII. 
The synthesis of compound 88 is shown below in Scheme XXIX. 
The syntheses of compounds 93, and 94 are shown below in Scheme XXX. 
The syntheses of compounds 95, and 96 are shown below in Scheme XXXI. 
The synthesis of compound 97 is shown below in Scheme XXXII. 
The syntheses of compounds 98, and 99 are shown below in Scheme XXXIII. 
The synthesis of compound 100 is shown below in Scheme XXXIV. 
The syntheses of compounds 101, and 102 are shown below in Scheme XXXV. 
The syntheses of compounds 103, and 104 are shown below in Scheme XXXVI. 
The syntheses of compounds 106, 107, and 108 are shown below in Scheme XXXVII. 
The syntheses of compounds 109, and 110 are shown below in Scheme XXXVIII. 
The syntheses of compounds 111, and 112 are shown below in Scheme XXXIX. 
The synthesis of compound 113 is shown below in Scheme XL. 
The syntheses of compounds 114, 115, 116, and 117 are shown below in Scheme XLI. 
The synthesis of compound 118 is shown below in Scheme XLII. 
The syntheses of compounds 123 and 124 are shown below in Scheme XLIII. 